WO2012034360A1 - Microsphère cristalline d'insuline, suspension et procédé de préparation associés - Google Patents

Microsphère cristalline d'insuline, suspension et procédé de préparation associés Download PDF

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Publication number
WO2012034360A1
WO2012034360A1 PCT/CN2011/001560 CN2011001560W WO2012034360A1 WO 2012034360 A1 WO2012034360 A1 WO 2012034360A1 CN 2011001560 W CN2011001560 W CN 2011001560W WO 2012034360 A1 WO2012034360 A1 WO 2012034360A1
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Prior art keywords
insulin
crystalline
polyethylene glycol
microspheres
solution
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PCT/CN2011/001560
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English (en)
Chinese (zh)
Inventor
梁伟
任武贤
魏秀莉
禹玉洪
于继兵
许振江
Original Assignee
中国科学院生物物理研究所
北京亚宝生物药业有限公司
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Publication of WO2012034360A1 publication Critical patent/WO2012034360A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • Insulin crystalline microspheres Insulin crystalline microspheres, suspensions thereof, and preparation methods
  • the invention belongs to the field of medicine and relates to an insulin crystalline microsphere suspension and a preparation method thereof. More specifically, it relates to an insulin crystalline microsphere suspension prepared by a liquid-phase crystallization technique and a preparation method thereof. Background technique
  • the oral administration route of insulin can simulate physiological insulin secretion, and the ratio of portal insulin concentration to peripheral circulating insulin concentration in the physiological state is approximately 1:5. Therefore, the oral delivery system is the most ideal non-injection route for insulin, avoiding The pain and inconvenience of the injection, the patient's compliance is strong.
  • the key problem to be solved by the insulin oral delivery system is how to prevent the insulin from being damaged by the enzyme in the gastrointestinal tract.
  • the currently reported preparation methods for insulin oral delivery systems are as follows: (1) addition of absorption enhancers: absorption enhancers include protease inhibitors and penetration enhancers, commonly used absorption enhancers include cholates, surfactants, Bacitracin and amino acid derivatives, and the like.
  • absorption enhancers can damage the gastrointestinal epithelium, affect the absorption of nutrients, and can also lead to the entry of bacterial toxins, which may cause systemic infections and toxic reactions;
  • Protection of insulin stability in the gastrointestinal tract by formulation techniques and promotion of its absorption include encapsulation of insulin in liposomes, solid microspheres/nanoparticles, micelles, hydrogels, Emulsions, etc.
  • formulation techniques include encapsulation of insulin in liposomes, solid microspheres/nanoparticles, micelles, hydrogels, Emulsions, etc.
  • the above preparation techniques all have certain limitations: poor stability of liposomes; organic solvents, high temperature/high pressure are often used in the preparation of nanoparticles/microspheres, and these undesirable conditions may cause insulin loss activity, and some polymer materials are in vivo.
  • the main problem is the high dose of oral administration, low bioavailability, and difficulty in clinical application.
  • the main focus is on how to overcome the enzyme barrier and intestinal epithelial barrier in the gastrointestinal tract, increase the permeability of the intestinal epithelium and open tight junctions, while ignoring the mucus layer on the surface of the gastrointestinal tract.
  • the effects of drug absorption are also important.
  • the human intestinal mucus layer consists of mucin, water, electrolytes, exfoliated epithelial cells, lipids, salts, enzymes, microorganisms and their products, up to several hundred microns thick.
  • Phospholipids make the mucus layer hydrophobic, and the mucin and water content determine the viscoelastic properties of the mucus layer. A small change in water content can make a very significant change in the rheological properties of the mucus.
  • the mucus layer contains a large amount of esterase and protein digestive enzyme, which is the main site of insulin degradation by enzymes.
  • the mucus layer is also a potential barrier to drug absorption.
  • the drug For oral delivery systems, regardless of the physicochemical properties of the drug, the drug must first pass through the mucus layer before it is absorbed through the epithelium.
  • the thickness of the mucus layer can significantly affect the rate at which macromolecules and charged molecular drugs enter the basal tissue.
  • the mucus layer can significantly delay the diffusion of hydrogen ions compared to water of equivalent thickness. Studies have shown that when the particles are larger than 60 nm, the mucus barrier cannot be worn.
  • the object of the present invention is to prepare a novel insulin oral delivery system, namely an insulin drug crystalline microsphere suspension, under the dual conditions of ensuring the effectiveness and safety of the insulin oral delivery system.
  • the invention provides an insulin drug crystalline microsphere suspension and a preparation method thereof, wherein the insulin drug crystal microspheres of a certain density and size are prepared by a liquid-phase crystallization technique. After lyophilizing the insulin crystalline microspheres to obtain insulin crystalline microspheres lyophilized powder, the suspension is suspended in a protective agent such as PEG or phospholipid to obtain an insulin microsphere suspension.
  • a protective agent such as PEG or phospholipid
  • the preparation of the microspheres does not rely on any polymer and organic solvent, thus ensuring the safety of the delivery system.
  • PEG' and pity are beneficial for the drug microspheres to rapidly pass through the intestinal mucus layer, avoid degradation by proteases, increase contact with intestinal lymphoid tissue, and promote drug absorption.
  • the rate at which the insulin crystalline microsphere suspension prepared by the present invention rapidly passes through the intestinal mucus layer can be achieved by the chain length of the PEG, the type of phospholipid, and the ratio between the PEG and the phospholipid.
  • the invention provides a preparation method of insulin crystalline microspheres, which comprises the following steps: (1) adding insulin to a salt solution, adding glacial acetic acid dropwise and stirring until the insulin is completely dissolved, adding an appropriate amount of polyethylene glycol, stirring Dissolved; the weight ratio of insulin to polyethylene glycol is 1:20-200;
  • step (2) adjusting the pH of the solution in step (1) to 3.5-4.5 to precipitate the precipitate; (3) heating and stirring the solution in step (2) until the precipitate is completely dissolved; (4) placing the solution at room temperature and adjusting the pH to 5.0-6.0, placed at 1-10 ° C (preferably 4 ° C), precipitates again; and (5) centrifuge, wash, and separate the precipitate to obtain insulin crystalline microspheres.
  • the method of the present invention further comprises the following steps: (6)
  • the obtained insulin crystalline microspheres are suspended in a polyethylene glycol solution and freeze-dried to obtain a lyophilized powder form of the insulin crystalline microspheres.
  • the polyethylene glycol solution is polyethylene glycol 2000 or polyethylene glycol 4000.
  • the salt solution is preferably a NaCl solution
  • the polyethylene glycol is polyethylene glycol 2000 or polyethylene glycol 4000.
  • the heating step has a temperature of 55 to 65 °C.
  • the washing process was washed 3 times with 0.5% NaCl, and then washed 3 times with a 0.5% polyethylene glycol 2000 solution.
  • the present invention also relates to an insulin crystalline microsphere obtained by the above method.
  • the invention also relates to an insulin crystalline microsphere suspension, which is microcrystallized from the above insulin The ball, a polar organic solvent and a lipophilic component.
  • the insulin crystalline microsphere suspension of the present invention contains less than 10% water.
  • the polar organic solvent is a polyethylene glycol.
  • the polyethylene glycol has a molecular weight of from 200 to 600, such as PEG 200, PEG 400.
  • the lipophilic component is a phospholipid.
  • the phospholipid is phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol or phosphatidylserine.
  • the weight/volume ratio (g/ml) of the insulin crystalline microspheres to polyethylene glycol and phospholipid is 1:1-100, in phospholipids and polyethylene glycols.
  • the weight/volume ratio (g/ml) is 0.001-0.05:1.
  • the insulin crystalline microsphere suspension of the present invention can be encapsulated in a soft capsule or a hard capsule.
  • the soft and hard capsules are enteric capsules or enteric coated.
  • the invention further relates to a method for preparing an insulin drug crystalline microsphere suspension, which comprises suspending the above insulin drug crystalline microspheres in a phospholipid-containing PEG solution to obtain an insulin microsphere suspension.
  • the present invention also relates to the use of the above-mentioned insulin drug crystalline microspheres or the above-mentioned insulin drug crystal microsphere suspension in the preparation of an oral hypoglycemic agent.
  • the size of the drug-crystallized microsphere of the present invention is ⁇ ⁇ or less, preferably 5 ⁇ m or less.
  • the invention has the advantages that: the degeneration of insulin caused by ⁇ and temperature change during microcrystallization can be reduced, and the activity is lost.
  • the freeze-drying step has no effect on the biological activity of insulin.
  • the dose of oral administration of insulin drug crystal microspheres is appropriate. When the dose of oral administration of 50 IU/kg is normal, the percentage of blood glucose lowering is 25%. It has broad clinical application prospects and can avoid the series of long-term injection of diabetes patients. side effect.
  • the insulin drug microsphere suspension of the present invention can be used for oral administration.
  • Figure 2 Determination of the particle size analyzer of insulin crystalline microsphere suspension
  • Figure 3 Changes in blood glucose levels after duodenal administration in normal rats with fasting anesthesia
  • Figure 7 Changes in blood glucose levels after administration of insulin-crystallized microsphere suspensions containing different phospholipids in the duodenum of normal rats
  • Fig. 8 Variation of blood glucose level after administration of insulin crystallization microsphere suspension containing different PEG chain length in duodenum of normal rats
  • Example 2 Place at 4 ° C for 12 h, lOOO r / min (TDZ5-WS multi-tube rack automatic balance centrifuge, rotor-2), centrifuge for 10 min, the resulting precipitate was washed 3 times with 0.5% NaCl aqueous solution, then 0.5% PEG 2000 The aqueous solution was washed 3 times, and the resulting precipitate was suspended in 1 ml of a 0.5% aqueous solution of PEG 2000, and lyophilized to obtain crystalline microspheres of insulin.
  • the structure of the insulin crystalline microspheres (Fig. 1) and the particle diameter distribution (Fig. 2) were determined by a low temperature scanning electron microscope and a particle size analyzer based on centrifugation and light transmission of solid particles.
  • the insulin content of the microspheres was determined by HLPC, and the insulin microspheres were obtained by grinding and suspending the insulin crystal microspheres in a PEG 200 solution containing 2.0% soybean phospholipid according to the requirements of the animal test.
  • Example 3 Place at 4 ° C for 16 h, 1000 r / min (TDZ5-WS multi-tube rack automatic balance centrifuge, rotor-2), centrifuge for 10 min, the resulting precipitate was washed 3 times with 0.8% NaCl aqueous solution, then 0.5% PEG The 2000 aqueous solution was washed 3 times, and the resulting precipitate was suspended in 1.5 ml of 0.5% PEG 2000 solution, and lyophilized to obtain insulin crystalline microspheres (Fig. 1, Fig. 2). The insulin content of the microspheres was determined by HLPC, and the insulin crystalline microspheres were ground and suspended in a PEG 400 solution containing 1.0% soybean phospholipid according to the needs of the animal test to obtain an insulin crystalline microsphere suspension.
  • Example 3 Example 3
  • Example 4 Place at 4 ° C overnight, 1000 r / min (TDZ5-WS multi-tube rack automatic balance centrifuge, rotor-2), centrifuge for 10 min, the resulting precipitate was washed 3 times with 0.5% NaCl aqueous solution, then 0.5% PEG 4000 aqueous solution After washing 3 times, the resulting precipitate was suspended in 1 ml of 0.5% PEG 4000 aqueous solution, and lyophilized to obtain crystalline microspheres of insulin (Fig. 1, Fig. 2). The content of insulin in the microspheres was measured by HLPC, and the insulin microspheres were obtained by grinding and suspending the insulin crystal microspheres in a PEG 200 solution containing 2.0% soybean phosphoester according to the needs of the animal test.
  • Example 4 The content of insulin in the microspheres was measured by HLPC, and the insulin microspheres were obtained by grinding and suspending the insulin crystal microspheres in a PEG 200 solution containing 2.0% soybean phosphoester according to the needs of the animal
  • Example 5 Place at 4 ° C overnight, 1000 r / min (TDZ5-WS multi-tube rack automatic balance centrifuge, rotor-2), centrifuge for 10 min, the resulting precipitate was washed 3 times with pH 5.7 0.5% NaCl aqueous solution, then 0.5% PEG The 4000 aqueous solution was washed 3 times, and the resulting precipitate was suspended in 2.5 ml of 0.5% PEG 4000 aqueous solution, and lyophilized to obtain crystalline microspheres of insulin (Fig. 1, Fig. 2). The insulin content of the microspheres was determined by HLPC, and the insulin crystal microspheres were ground and suspended in a PEG 400 solution containing 1.0% soybean phospholipid according to the needs of the animal test to obtain an insulin microsphere suspension.
  • Example 5 Example 5
  • Example 6 Place at 4 ° C overnight, 1000 r / min (TDZ5-WS multi-tube rack automatic balance centrifuge, rotor-2), centrifuge for 10 min, the resulting precipitate with pH 5.6 0.5% NaCl aqueous solution 3 times, then use 0.5% PEG 4000 The aqueous solution was washed 3 times, and the resulting precipitate was suspended in 2 ml of 0.5% PEG 4000 aqueous solution, and lyophilized to obtain crystalline microspheres of insulin (Fig. 1, Fig. 2). The content of insulin in the microspheres was determined by HLPC, and the insulin microspheres were obtained by grinding and suspending the insulin crystal microspheres in a PEG 400 solution containing 1.0% soybean phosphonite according to the needs of the animal test.
  • Example 6 Example 6
  • a small needle should be used as far as possible, and the drug should be injected downward along the intestinal tract.
  • Barbital sodium ensuring that the rats were always anesthetized during the test.
  • Blood was taken from the tail vein of rats at 0, 0.5, 1, 2, 3, 4, 6, 8, 10 h, and blood glucose levels were measured with a blood glucose meter. (Fig. 3) It can be seen from the figure that the blood glucose levels of the three groups increased during the 30 minutes after administration, and then decreased.
  • the blood glucose changes in the control group and the insulin solution group were basically the same, insulin drug microsphere suspension group
  • the blood glucose level was significantly lower than that of the control group and the insulin solution group, and the blood glucose level showed a downward trend within 4-8 h.
  • the blood glucose level dropped to the lowest level, about 30% of the initial value, and then the blood glucose began to rise. It is indicated that the anesthetized fasting rat has a significant hypoglycemic effect after administration of the insulin drug microsphere suspension in the duodenum.
  • a small needle should be used as far as possible and administered downward in the direction of the intestine. Subsequently, the abdomen of the rats was surgically sutured, and the rats were completely awake at about 1.5 h, and blood was taken from the tail veins of the rats at 3, 4, 6, 8, and 10 h, respectively, and blood glucose levels were measured by a blood glucose meter (Fig. 4). It can be seen from the figure that the blood glucose changes in the control group and the insulin solution group are basically the same, and the blood glucose level in the insulin drug microsphere suspension group is significantly lower than that in the control group and the insulin solution. In group, blood glucose dropped to the lowest level at 4 h, about 25% of the initial value, and then blood sugar began to rise.
  • the relationship between the amount of insulin crystalline microspheres and the hypoglycemic effect in vivo was investigated in normal rats.
  • 15 healthy male Sprague-Dawley rats weighing 180-200 g were randomly divided into 3 groups. The first group was given insulin drug microsphere suspension (50 IU.kg-l), and the second group was given insulin drug microsphere suspension. (200 IU.kg-l), the third group was given insulin drug microsphere suspension (500 IU.kg-l).
  • the rats were anesthetized with intraperitoneal injection of pentobarbital sodium.
  • the rats were fixed on the abdomen with the abdomen facing up.
  • the abdominal cavity was opened along the midline of the rat and the duodenum was administered.
  • the effect of the amount of phospholipid on the biofilm effect of insulin crystalline microspheres was investigated in normal rats. Twenty healthy male Sprague-Dawley rats, weighing 180-200 g, were randomly divided into 4 groups. The first group was given a phospholipid-free insulin drug microsphere suspension, and the second group was given an insulin drug microsphere suspension containing 1% phospholipid. In the third group, an insulin drug microsphere suspension containing 5% phospholipid was administered, and the fourth group was administered an insulin drug microsphere suspension containing 10% phospholipid. Fasting for 16 h before the experiment, free to drink. Rats were anesthetized with intraperitoneal injection of pentobarbital sodium. The rats were fixed on the plate with the abdomen facing up.
  • the abdominal cavity was opened along the midline of the rat and the duodenum was administered.
  • the specific operation was as follows: Injection at a distance of about 5 cm from the pylorus medicine. In order to avoid spillage of the solution, a small needle should be used as far as possible and administered downward in the direction of the intestine. Subsequently, the abdomen of the rats was surgically sutured, and blood was taken from the tail vein of the rats at 0.5, 1, 2, 3, 4, 5, 6, and 8 h, respectively, and blood glucose levels were measured by a blood glucose meter (Fig. 7). As can be seen from the figure, the presence or absence of phospholipids in the insulin microsphere suspension of insulin is essential.
  • PEG 4000 refers to 25% PEG4000 in PEG 400
  • insulin crystalline microspheres 200 IU.kg-l
  • Rats were anesthetized with intraperitoneal injection of pentobarbital sodium. The rats were fixed on the plate with the abdomen facing up, and the abdominal cavity was opened along the midline of the rat's abdomen. The duodenum was administered as follows: Injection at a distance of about 5 cm from the pylorus medicine.

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Abstract

L'invention concerne une microsphère cristalline d'insuline, sa suspension et un procédé de préparation associés. La microsphère cristalline d'insuline est préparée par un procédé d'agglomération sous forme de bille et de cristallisation dans un liquide qui utilise le point isoélectrique de l'insuline. La microsphère cristalline d'insuline a un diamètre moyen de 1-10µm. La suspension de microsphères cristallines d'insuline est formée par la mise en suspension de la microsphère cristalline d'insuline lyophilisée dans des agents protecteurs tels que PEG et des phospholipides, etc.
PCT/CN2011/001560 2010-09-15 2011-09-14 Microsphère cristalline d'insuline, suspension et procédé de préparation associés WO2012034360A1 (fr)

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CN2010102847832A CN102397535B (zh) 2010-09-15 2010-09-15 胰岛素结晶微球、其混悬剂、以及制备方法
CN201010284783.2 2010-09-15

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
US20220339114A1 (en) * 2021-04-17 2022-10-27 Bhami's Research Laboratory, Pvt. Ltd. Polypeptide formulations

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RU2014120626A (ru) * 2014-05-22 2015-11-27 Владимир Андреевич Сабецкий Инсулинсодержащий препарат пролонгированного действия

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CN1425464A (zh) * 2002-12-26 2003-06-25 西安交通大学 口服胰岛素纳米材料的制备工艺
CN1562356A (zh) * 2004-03-19 2005-01-12 中国科学院长春应用化学研究所 载有胰岛素的生物降解高分子微球及其制备方法
CN101199482A (zh) * 2007-12-20 2008-06-18 中国科学院长春应用化学研究所 包裹纳米胰岛素的生物可降解聚酯微球制备方法

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KR100508695B1 (ko) * 2001-02-13 2005-08-17 한국과학기술연구원 인슐린의 경구투여용 제형과 그의 제조방법
CN1160122C (zh) * 2001-04-20 2004-08-04 清华大学 一种制备口服胰岛素油相制剂的方法
CN101618023B (zh) * 2008-06-30 2011-11-30 江苏先声药物研究有限公司 一种制备微粉化蛋白的方法

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CN1425464A (zh) * 2002-12-26 2003-06-25 西安交通大学 口服胰岛素纳米材料的制备工艺
CN1562356A (zh) * 2004-03-19 2005-01-12 中国科学院长春应用化学研究所 载有胰岛素的生物降解高分子微球及其制备方法
CN101199482A (zh) * 2007-12-20 2008-06-18 中国科学院长春应用化学研究所 包裹纳米胰岛素的生物可降解聚酯微球制备方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220339114A1 (en) * 2021-04-17 2022-10-27 Bhami's Research Laboratory, Pvt. Ltd. Polypeptide formulations

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